Field of the Invention
The present invention relates to reducing or inhibiting cardiac dysfunction due to heart failure by administering a bisphosphonate compound.
Related Art in the Field
The prevalence of heart failure (“HF”) has grown to epidemic proportions as the population ages and as cardiologists have become more successful at reducing mortality from ischemic heart disease, the most common prelude to HF. Specifically, more than 5.7 million Americans suffer from heart failure, and an estimated 550,000 new cases are diagnosed each year (Lloyd-Jones et al. 2009). Despite current treatment options, patients with stage II or III heart failure face a 2-year mortality rate of 25%, poor quality of life, and repeated hospitalizations to manage acute decompensations. The American Heart Association estimates the direct and indirect cost of heart failure in the United States to be $37.2 billion dollars in 2009 alone (Lloyd-Jones et al. 2009).
HF may be caused by many forms of heart disease. Common causes of heart failure include: narrowing of the arteries supplying blood to the heart muscle (coronary heart disease); prior heart attack (myocardial infarction) resulting in scar tissue large enough to interfere with normal function of the heart; high blood pressure; heart valve disease due to past rheumatic fever or an abnormality present at birth; primary disease of the heart muscle itself (cardiomyopathy); and infection of the heart valves and/or muscle itself (endocarditis and/or myocarditis). Each of these disease processes can lead to heart failure by reducing the strength of the heart muscle contraction, by limiting the ability of the heart's pumping chambers to fill with blood due to mechanical problems or impaired diastolic relaxation, or by filling the heart's chambers with too much blood.
Cardiac dysfunction due to cardiotoxicity can also be caused by radiation-induced heart disease (RIHD) and chemotherapeutic agents which are caused by therapeutic interventions to treat malignancies. Cardiotoxicity renders the heart unable to efficiently pump blood throughout the body. Symptoms of this effect include shortness of breath, fatigue, and anemia. These signals indicate that the heart is having difficulty maintaining its essential function. It has also been found that radiation therapy (RT) can cause injury to all the components of the heart, including the damage of small vessels that supply the blood to the heart. It may cause scarring in the heart muscle. Further, the coronary arteries are more prone to clotting after being treated with radiation. The radiation may damage the endothelial lining of the vessels making them form clots more readily. As stated above, the chemotherapeutic agent used in cancer treatment, such as anthracyclines, alkylating agents, antimetabolites, antimicrotubules and etc. can also cause cardiotoxicity.
The dominant pathophysiology associated with HF is systolic dysfunction, an impairment of cardiac contractility (with a consequent reduction in the amount of blood ejected with each heartbeat). Systolic dysfunction with compensatory dilation of the ventricular cavities results in the most common form of heart failure, “dilated cardiomyopathy.” The counterpoint to systolic dysfunction is diastolic dysfunction, an impairment of the ability to fill the ventricles with blood, which can also result in heart failure even with preserved left ventricular function. Heart failure is ultimately associated with improper function of the cardiac muscle cells involving a decrease in the ability to effectively contract and relax.
Many of the same underlying conditions can give rise to systolic and/or diastolic dysfunction, such as atherosclerosis, hypertension, viral infection, valvular dysfunction, and genetic disorders. Patients with these conditions typically present with the same classical symptoms: shortness of breath, edema and overwhelming fatigue. In approximately half of the patients with dilated cardiomyopathy, the cause of their heart dysfunction is ischemic heart disease due to coronary atherosclerosis. These patients have had either a single myocardial infarction or multiple myocardial infarctions and the consequent scarring and remodeling results in the development of a dilated and hypocontractile heart.
A more recent finding is that inflammatory cytokines are elevated in patients with heart failure. Indeed, there is a direct relationship between elevated levels of TNF-α and IL-6 and the degree of hemodynamic abnormalities. Similarly, the higher the TNF-α level the more severe the heart failure symptoms. Interestingly, it has been found that TNF-α is not expressed by normal human heart but is expressed in abundant amounts by human failing heart. Furthermore, TNF-α can induce the expression of other inflammatory cytokines.
Numerous compounds are known to be useful for the prevention and treatment of heart failure, including alpha-adrenergic antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic antagonists, antihypertensives, calcium channel blockers, diuretics, potassium channel opening vasodilators, renin inhibitors, and serotonin antagonists. However, in view of the high prevalence of heart failure in the general population and the poor prognosis of these patients, there remains a great need for agents that exploit new mechanisms of action and may have better outcomes in terms of relief of symptoms, safety, and patient mortality, both short-term and long-term. New agents may provide a means to achieve better clinical outcomes for those who have or are at risk for heart failure.